Susceptibility to multiple sclerosis (MS) is linked to genes of the immunoglobulin supergene family, including the HLA class II genes, genes encoding the immunoglobulins, and genes encoding the T cell receptor (TCR). We and others have previously described germline polymorphisms in lg and TCR V genes associated with susceptibility to MS. Using PCR technology we have amplified rearranged TCR Valpha and Vbeta genes directly from MS brain plaque. There is limited diversity of TCR Valpha and Vbeta gene rearrangements in areas of demyelination. Sequencing further reveals limited junctional diversity. Finally, in a particular molecular phenotype HLA-DRB1 *1501, DQA1*0102, DQB1*0602, DPB1*0401, associated with the HLA-DR2Dw2 haplotype linked to MS, there is preferential rearrangement of Vbeta5.2 and Vbeta6. Based on animal models such observations may have clinical relevance. We have shown that antibodies to TCR V gene products, as well as to class II histocompatibility molecules, associated with susceptibility to experimental autoimmune encephalomyelitis have been used successfully to treat clinical paralysis in mice. Identification of HLA class II and TCR V genes involved in the pathogenesis of MS may allow us to design therapies in man, similar to that which we have used successfully in experimental animals.